Serotherapy against Voltage-Gated Sodium Channel-Targeting α-Toxins from Androctonus Scorpion Venom Marie-France Martin-Eauclaire, Sonia Adi-Bessalem, Djelila Hammoudi-Triki, Fatima Laraba-Djebari, Pierre Bougis To cite this version: Marie-France Martin-Eauclaire, Sonia Adi-Bessalem, Djelila Hammoudi-Triki, Fatima Laraba-Djebari, Pierre Bougis. Serotherapy against Voltage-Gated Sodium Channel-Targeting α-Toxins from Androc- tonus Scorpion Venom. Toxins, MDPI, 2019, 11 (2), pp.63. 10.3390/toxins11020063. hal-02553333 HAL Id: hal-02553333 https://hal.archives-ouvertes.fr/hal-02553333 Submitted on 24 Apr 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. toxins Review Serotherapy against Voltage-Gated Sodium Channel-Targeting α-Toxins from Androctonus Scorpion Venom Marie-France Martin-Eauclaire 1, Sonia Adi-Bessalem 2,†, Djelila Hammoudi-Triki 2,†, Fatima Laraba-Djebari 2,† and Pierre E. Bougis 1,* 1 Laboratory of Cognitive Neuroscience, CNRS, Aix Marseille Univ, UMR 7291, 13003 Marseille, France; [email protected] 2 Laboratory of Cellular and Molecular Biology, Faculty of Biological Sciences, USTHB, BP 32, El-Alia Bab Ezzouar, 16111 Algiers, Algeria; [email protected] (S.A.-B.); [email protected] (D.H.-T.); fl[email protected] (F.L.-D.) * Correspondence: [email protected]; Tel.: +33-4-9169-8850 † These authors contributed equally. Received: 23 November 2018; Accepted: 21 January 2019; Published: 23 January 2019 Abstract: Because of their venom lethality towards mammals, scorpions of the Androctonus genus are considered a critical threat to human health in North Africa. Several decades of exploration have led to a comprehensive inventory of their venom components at chemical, pharmacological, and immunological levels. Typically, these venoms contain selective and high affinity ligands for the voltage-gated sodium (Nav) and potassium (Kv) channels that dictate cellular excitability. In the well-studied Androctonus australis and Androctonus mauretanicus venoms, almost all the lethality in mammals is due to the so-called α-toxins. These peptides commonly delay the fast inactivation process of Nav channels, which leads to increased sodium entry and a subsequent cell membrane depolarization. Markedly, their neutralization by specific antisera has been shown to completely inhibit the venom’s lethal activity, because they are not only the most abundant venom peptide but also the most fatal. However, the structural and antigenic polymorphisms in the α-toxin family pose challenges to the design of efficient serotherapies. In this review, we discuss past and present accomplishments to improve serotherapy against Androctonus scorpion stings. Keywords: Androctonus; scorpion; venom; toxin; Nav channel; serotherapy Key Contribution: This review summarizes the most relevant developments in the field of serotherapy against scorpion stings of the genus Androctonus. 1. Introduction Scorpions comprise around 2400 species, and belong to an ancient and ecologically successful group of animals that has been exemplified in the fossil record for some 400 million years [1,2]. They pose a public health threat in many countries, but particularly in North Africa [3,4]. Scorpions most dangerous for humans belong to the Buthidae family, which, with 82 genera and 756 species, is the largest scorpion family, found on every continent except Antarctica [5,6]. About twenty Buthidae species are known to be lethal to humans. Some of these lethal species belong to the Androctonus genus, as A. australis in Algeria (Hector morph) and in Tunisia (garzonii sub-species) and A. mauretanicus in Morocco. These sizeable animals can inoculate up to 500 µg of a venom that is particularly rich in toxins. In the Maghreb, these two species are responsible for about 100,000 stings per year and, 1 to 7% lead to death [7]. Their median lethal dose (LD50) by subcutaneous (s.c.) injection is between 1 and 5 Toxins 2019, 11, 63; doi:10.3390/toxins11020063 www.mdpi.com/journal/toxins Toxins 2019, 11, 63 2 of 23 µg per mouse (20 g), and they are therefore considered to be the most lethal scorpion species in the world for mammals and humans [8,9]. Other venomous Androctonus species are Androctonus amoreuxi, Androctonus aeneas aenaes, Androctonus crassicauda, and Androctonus bicolor. However, the chemical and pharmacological properties of their venoms are still poorly studied, compared to what is currently known about the Androctonus australis and Androctonus mauretanicus venoms. The three Pasteur Institutes in Maghreb have largely added to our knowledge of the Androctonus mauretanicus and Androctonus australis venoms, their main objective being the production of specific and efficient antivenoms for serotherapy purposes [10–12]. Victims of scorpion stings suffer various pathologies, involving both sympathetic and parasympathetic stimulation as well as central manifestations such as irritability, hyperthermia, vomiting, profuse salivation, tremor, and convulsions. The clinical signs and symptoms observed in humans and experimental animals are related to an excessive systemic host inflammatory response to stings. In addition to cardiac dysfunction, pulmonary edema, and respiratory failure, systemic inflammatory response seems to be strongly implicated in the pathogenesis of scorpion envenomation. The complexity of scorpion pathogenesis and its severity reduces the efficacy of treatment. Thus, improving serotherapy is a key challenge for scientists and antiserum producers. Scorpion venoms are complex mixtures of peptides and proteins, for which many have yet to be assigned a function. The polypeptide toxins from scorpion venom have very specific actions, and mainly interact with different ion channels and receptors in excitable membranes. Four different families of scorpion neurotoxins have been described, which specifically recognize voltage-gated sodium, voltage-gated potassium, voltage-gated calcium, and chloride channels [13]. These neurotoxins are present in the venom as a few percent of the dried venom weight. In Androctonus venoms, s.c. venom toxicity in mammals has mainly been attributed to the activity of long polypeptide chain toxins, which bind with high affinity to voltage-gated sodium (Nav) channels [14,15]. Indeed, Nav channels are very critical for generating the rising phase of an action potential by promoting a rapid flux of ions across the membrane [16], an action that is disrupted by scorpion toxins. With their high number of disulfide bonds (four), which hold together their rather small molecular size (60–70 residues), these toxins can persist in a hostile environment because they are highly stable and resistant to denaturation. They display a high degree of relatedness at the level of three-dimensional (3D) structure, despite having more limited sequence homology. Neutralization of scorpion venoms by heterologous antivenoms has been extensively investigated. However, the effectiveness of each commercial available antivenom, produced in a different geographical area, in neutralizing homologous and heterologous scorpion venoms has been a matter of debate [17]. Nowadays, antivenom specificity can be explained by the large amount of chemical and immunological data accumulated so far. In this review, we will tackle recent research progress that led to our understanding of (1) the mechanisms contributing to the pathophysiology and inflammatory response after envenomation, (2) the chemistry of Androctonus venom α-toxins and their immunochemical interrelations, and (3) the set-up of an appropriate serotherapy with the most recent developments, and possible future directions. 2. Immediate Envenomation Symptoms Commonly, the symptoms of scorpion stings are mainly observed in the peripheral nervous system. Stings in children, the elderly, and immunocompromised people are much more dangerous than in healthy adults. Following a sting, symptom progression is rapid. However, serotherapy is very effective when a specific antiserum is rapidly injected; victims typically recover within one hour after administration. Three stages of severity are described [18]. First, an immediate intense and persistent pain (up to two hours) is the dominant clinical sign. During this unthreatening stage I, other discrete general symptoms can be observed such as agitation, febricula, sweats, nausea, feeling of general faintness, and alternating blood pressure (hypertension or hypotension). During stage II, which Toxins 2019, 11, 63 3 of 23 is considered a severe envenomation, the body temperature increases and sweats, epigastric pain, vomiting, colic, diarrhea, priapism, hypotension, bradycardia, pulmonary obstruction, and dyspnea can appear. Vomiting indicates huge severity and necessitates specific monitoring. Stage III is only seen in 5–10% of stage II cases, and is potentially fatal. At this late stage, cardiac arrhythmia and myocardial ischemia explain the risk of cardiovascular collapse, associated with severe respiratory complications such as pulmonary edema, bronchospasm, and cyanosis.